Studies In Epidemiology Group Research Articles

Inappropriate Methods May Lead to Misleading Conclusions From the Meta-analysis of Observational Studies.

To the Editors: We read the article by Renko and colleagues with the outmost interest.1 This article discusses an important and relevant aspect of urinary tract infection (UTI) for pediatricians. The authors in this article systematically reviewed and synthesized data on risk factors for UTI in children. Twenty-four studies were included in the meta-analysis. Authors found that circumcision and breastfeeding reduce the risk of UTI, and poor fluid intake, infrequent voiding, and being overweight or obese increase the risk of UTI recurrence in children. More importantly, the authors also observed that obstipation and high-grade vesicoureteric reflux do not increase the risk of recurrent UTIs. Overall, this article addresses an important issue for clinicians, but we came across a few methodological concerns, which may affect the validity of the findings of this meta-analysis. It is usually recommended that the literature search be comprehensive (at least 2–3 bibliographic electronic databases) before conducting a meta-analysis. Systematic reviews of observational studies require an even more robust literature search.2,3 Authors performed a literature search only in 1 database (PubMed); hence, the likely possibility that few studies may have been missed putting this systematic review at higher risk of publication bias. In this article, authors did not report publication bias, which was not discussed under limitations. A few missed studies (Gondim et al. 2018, Shaikh et al. 2016, Conway et al. 2007, and Cho et al. 2005) that assess risk factors for UTI are missed. High-grade VUR and bladder-bowel dysfunction (BBD) are 2 widely recognized and reported risk factors for UTI. Still, the present meta-analysis failed to demonstrate these risk factors for recurrence of UTI, as the literature search was not extensive and missed studies. The authors state that they have followed the checklist of the Meta-analysis of Observational Studies in Epidemiology group (MOOSE) but failed to report the search strategy for literature search, which is an essential component per this MOOSE guidance. In the current risk-stratification model for recurrence of UTI, age, sex, VUR severity, BBD, and circumcision status are considered important factors.4 However, the authors in this meta-analysis did not assess age and sex as risk factors and failed to show the other 2 factors (BBD and VUR) as risk predictors for recurrent UTI in children. Similarly, some studies (Ellison et al. 2018, Dubrovsky et al. 2015, Braga et al. 2015, Alsaywid et al. 2010, Nayir et al. 2001) assessing the circumcision status as a risk factor for UTI are also missed.5 These findings are likely caused by a suboptimal literature search and an inappropriate study selection process. The authors mention low heterogeneity in the text, but it has not been reported for most risk factors except I2 –7.5% for circumcision status. Furthermore, the authors do not explicitly report what was considered severe congenital renal abnormalities as they used it as one of the exclusion criteria. Although they included studies with VUR grade IV and V, we feel that these limitations could have been better discussed in the limitation section because these may have had a significant impact on this meta-analysis’s finding.

Quantifying the prognostic significance of microRNA-17/17-5P in cancers: a meta-analysis based on published studies.

ObjectiveThe aim of this study was to investigate the prognostic value of mircoRNA-17 and mircoRNA-17-5P (miR-17/17-5P) in patients with cancer.Materials and methodsWe conducted a comprehensive search on published literature following the guidelines of the meta-analysis of observational studies in epidemiology group for design, implementation, and reporting. The methodological qualities for included studies were assessed using the quality in prognosis studies. The pooled hazard ratios (HRs) with 95% CIs for overall survival (OS) and progression-free survival/recurrence-free survival/disease-free survival (PFS/RFS/DFS) were calculated to appraise the associations between miR-17/17-5P expression and cancer prognosis.ResultsA total of 21 studies involving 2099 subjects were analyzed in evidence synthesis. The results showed that high expression of miR-17 was associated with poor OS (HR=2.14; 95% CI: 1.69–2.71, P<0.001) in patients with cancer, especially in Caucasian (HR=2.23; 95% CI: 1.58–3.14, P<0.001) and digestive tract cancer (HR=1.29, 95% CI: 1.03–1.63, P=0.03), and miR-17 expression was significantly correlated with PFS/RFS in cancer patients (HR=1.69, 95% CI: 1.29–2.22, P<0.001). miR-17-5P overexpression was significantly linked with poor OS in cancer patients (HR=1.66; 95% CI: 1.31–2.09, P=0.00), especially in Asian (HR=1.81; 95% CI: 1.37–2.40, P<0.001), digestive tract cancer (HR=1.80; 95% CI: 1.29–2.50, P<0.001), and serum sample (HR=1.76; 95% CI: 1.29–2.41, P<0.001). miR-17-5P expression was significantly associated with DFS in cancer patients (HR=1.58, 95% CI: 1.07–2.35, P=0.02).ConclusionHigh expression of miR-17 and miR-17-5P are significantly associated with poor survival in patients with cancer. This indicated that miR-17/17-5P may be a novel prognostic indicator in cancer.

A Comparison of the Quick-SOFA and Systemic Inflammatory Response Syndrome Criteria for the Diagnosis of Sepsis and Prediction of Mortality: A Systematic Review and Meta-Analysis

Several studies were published to validate the quick Sepsis-related Organ Failure Assessment (qSOFA), namely in comparison with the systemic inflammatory response syndrome (SIRS) criteria. We performed a systematic review and meta-analysis with the aim of comparing the qSOFA and SIRS in patients outside the ICU. We searched MEDLINE, CINAHL, and the Web of Science database from February 23, 2016 until June 30, 2017 to identify full-text English-language studies published after the Sepsis-3 publication comparing the qSOFA and SIRS and their sensitivity or specificity in diagnosing sepsis, as well as hospital and ICU length of stay and hospital mortality. Data extraction from the selected studies followed the recommendations of the Meta-analyses of Observational Studies in Epidemiology group and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. From 4,022 citations, 10 studies met the inclusion criteria. Pooling all the studies, a total of 229,480 patients were evaluated. The meta-analysis of sensitivity for the diagnosis of sepsis comparing the qSOFA and SIRS was in favor of SIRS (risk ratio [RR], 1.32; 95%CI, 0.40-2.24; P<.0001; I2= 100%). One study described the specificity for the diagnosis ofinfection comparing SIRS (84.4%; 95%CI, 76.2-90.6) with the qSOFA (97.3%; 95%CI<92.1-99.4); the qSOFA demonstrated better specificity. The meta-analysis of the area under the receiver operating characteristic curve of six studies comparing the qSOFA and SIRS favored the qSOFA (RR, 0.03; 95%CI, 0.01-0.05; P= .002; I2= 48%) as a predictor of inhospital mortality. The SIRS was significantly superior to the qSOFA for sepsis diagnosis, and the qSOFA was slightly better than the SIRS in predicting hospital mortality. The association of both criteria could provide a better model to initiate or escalate therapy in patients with sepsis. PROSPERO CRD42017067645.

Vitamin D and risk of preeclampsia: A systematic review and meta-analysis.

Human vitamin D levels have been increasingly related to a wide range of clinical outcomes. There is a large amount of reports on its associations, especially with obstetric complications, including preeclampsia and gestational diabetes. These results are scarcely consistent and there is still a lack of quality intervention studies to confirm the role of vitamin D in those outcomes. Objective: To review the available scientific evidence on the role of maternal vitamin D in the development of preeclampsia. The methodology used followed the recommendations of the Cochrane guide for the preparation of systematic reviews, and for metaanalysis, the Guide of the Metaanalysis of Observational Studies in Epidemiology group (MOOSE). The search included both observational studies and controlled clinical trials. Low vitamin D levels, measured by the 25-hydroxyvitamin D test, are common in pregnancy. The results of this systematic review and metaanalysis suggest an inverse ratio between vitamin D levels and the development of preeclampsia. There was heterogeneity among the studies with regard to the design, population, geographic location, definitions of exposure, and the outcome. We excluded randomized controlled trials from this meta-analysis. The inverse association we found suggests that the higher the levels of vitamin D the lesser the probability of developing preeclampsia, in spite of the heterogeneity of the global measurement in this type of analysis.

The clinical association of programmed cell death protein 4 (PDCD4) with solid tumors and its prognostic significance: a meta-analysis.

BackgroundProgrammed cell death protein 4 (PDCD4) is a novel tumor suppressor protein involved in programmed cell death. Its association with cancer progression has been observed in multiple tumor models, but evidence supporting its association with solid tumors in humans remains controversial. This study aimed to determine the clinical significance and prognostic value of PDCD4 in solid tumors.MethodsA systematic literature review was performed to retrieve publications with available clinical information and survival data. The eligibility of the selected articles was based on the criteria of the Dutch Cochrane Centre proposed by the Meta-analysis Of Observational Studies in Epidemiology group. Pooled odds ratios (ORs), hazard ratios (HRs), and 95% confidence intervals (CIs) for survival analysis were calculated. Publication bias was examined by Begg’s and Egger’s tests.ResultsClinical data of 2227 cancer patients with solid tumors from 23 studies were evaluated. PDCD4 expression was significantly associated with the differentiation status of head and neck cancer (OR 4.25, 95% CI 1.87–9.66) and digestive system cancer (OR 2.87, 95% CI 1.84–4.48). Down-regulation of PDCD4 was significantly associated with short overall survival of patients with head and neck (HR: 3.44, 95% CI 2.38–4.98), breast (HR: 1.86, 95% CI 1.36–2.54), digestive system (HR: 2.12, 95% CI 1.75–2.56), and urinary system cancers (HR: 3.16, 95% CI 1.06–9.41).ConclusionsThe current evidence suggests that PDCD4 down-regulation is involved in the progression of several types of solid tumor and is a potential marker for solid tumor prognoses. Its clinical usefulness should be confirmed by large-scale prospective studies.

Prognostic significance of low microRNA-218 expression in patients with different types of cancer: Evidence from published studies.

Background:Mounting evidence showed that microRNAs may be useful as prognostic biomarkers of cancer. Therefore, we summarize the predictive role of microRNA-218 (miR-218) for survival in patients with various cancers.Methods:We performed a systematic literature review and assessed the quality of included studies based on Meta-analysis of Observational Studies in Epidemiology group (MOOSE). Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were calculated to assess the correlation between miR-218 expression and prognosis of different cancers.Results:We identified 10 studies for pooled analyses. For overall survival, a lower expression levels of miR-218 significantly predicted poorer survival, with the pooled HR of 2.61 (95% CI: 2.11–3.22, P < 0.001). For disease-free survival/progressive-free survival/recurrence-free survival (DFS/PFS/RFS), a lower expression level of miR-218 significantly predicted worse DFS/PFS/RFS in various carcinomas, with the pooled HR of 2.73 (95% CI: 2.08–3.58, P < 0.001). Similarly, subgroup analysis by detection method, ethnicity and cancer subtype analysis suggested that lower expression of miR-218 correlated with.Conclusion:Our data demonstrated that lower miR-218 expression is significantly associated with poorer overall survival (OS) and DFS/PFS/RFS and may be a novel prognostic biomarker in some cancer types.

European Code against Cancer 4th Edition: Ionising and non-ionising radiation and cancer

Ionising radiation can transfer sufficient energy to ionise molecules, and this can lead to chemical changes, including DNA damage in cells. Key evidence for the carcinogenicity of ionising radiation comes from: follow-up studies of the survivors of the atomic bombings in Japan; other epidemiological studies of groups that have been exposed to radiation from medical, occupational or environmental sources; experimental animal studies; and studies of cellular responses to radiation. Considering exposure to environmental ionising radiation, inhalation of naturally occurring radon is the major source of radiation in the population – in doses orders of magnitude higher than those from nuclear power production or nuclear fallout. Indoor exposure to radon and its decay products is an important cause of lung cancer; radon may cause approximately one in ten lung cancers in Europe. Exposures to radon in buildings can be reduced via a three-step process of identifying those with potentially elevated radon levels, measuring radon levels, and reducing exposure by installation of remediation systems. In the 4th Edition of the European Code against Cancer it is therefore recommended to: “Find out if you are exposed to radiation from naturally high radon levels in your home. Take action to reduce high radon levels”. Non-ionising types of radiation (those with insufficient energy to ionise molecules) – including extremely low-frequency electric and magnetic fields as well as radiofrequency electromagnetic fields – are not an established cause of cancer and are therefore not addressed in the recommendations to reduce cancer risk.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Malignant Peritoneal Mesothelioma: A Systematic Review and Meta-analysis

Due to the increased adoption of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), patients with malignant peritoneal mesothelioma (MPM) have seen improved outcomes. We aimed to evaluate and synthesize the recent published literature. The review was conducted according to the recommendation of the Meta-Analysis of Observational Studies in Epidemiology group with prespecified inclusion and exclusion criteria. The DEALE method was used to combine mortality rates, and imputation techniques were used to calculate standard errors. Meta-regression techniques were used to synthesize data. Publication bias was assessed using funnel plots. Of 6,528 citations collected, 20 articles reporting on 1,047 patients were included in the analysis. The median age was 51years (interquartile range 49-55), with 59% (54-67) female. The median peritoneal carcinomatosis index score was 19 (16-23). Complete cytoreduction (CC0, 1) was performed in 67% (46-93%) of patients. Pooled estimates of survival yielded a 1-, 3- and 5-year survival of 84, 59, and 42%, respectively. Patients receiving early postoperative intraperitoneal chemotherapy [EPIC] (44%) and those receiving cisplatin intraperitoneal chemotherapy alone (48%) or in combination (44%) had an improved 5-year survival. While CRS+HIPEC has led to an improved survival for patients with MPM compared to historic data, heterogeneity of studies precludes generalizable inferences. EPIC chemotherapy and cisplatin chemoperfusion may infer survival benefit.

Systematic review of health outcomes in relation to salt intake highlights the widening divide between guidelines and the evidence.

See ARTICLE page 1129. Until recently, the salt debate remained dominated by a select group of highly vocal global leaders whose goal is to impose their views through an unbalanced interpretation of so-called compelling evidence. Sailing against the tide, in this issue of the Journal, Graudal and colleagues published a comprehensive review of the literature 1 that complied with the highest possible quality standards as proposed by the Meta-analysis of Observational Studies in Epidemiology group. 2 Data from 23 cohort studies and 2 follow-up studies of randomized controlled trials (n = 274,683 participants) showed that the risks of all-cause mortality or cardiovascular disease were higher at low and high vs. usual sodium intake, congruent with a U-shaped association between health outcomes and salt intake. 1 The hazard ratios of total mortality and cardiovascular disease for low vs. usual sodium intake were 1.10 (95% confidence interval (CI) = 1.01–1.22) and 1.11 (95% CI = 1.01–1.22), respectively. The corresponding hazard ratios for high vs. usual sodium exposure were 1.16 (95% CI = 1.03–1.30) and 1.12 (95% CI = 1.02–1.24). 1 Cardiovascular endpoints and 24-hour urinary sodium

Elite Athletes Live Longer Than the General Population: A Meta-Analysis

ObjectiveTo perform a meta-analysis of cohort studies aimed at providing an accurate overview of mortality in elite athletes. Patients and MethodsWe reviewed English-language scientific articles available in Medline and Web of Science databases following the recommendations of the Meta-analyses Of Observational Studies in Epidemiology group. We searched for publications on longevity and professional or elite athletes (with no restriction on the starting date and up to March 31, 2014). ResultsTen studies, including data from a total of 42,807 athletes (707 women), met all inclusion criteria. The all-cause pooled standard mortality ratio (SMR) was 0.67 (95% CI, 0.55-0.81; P<.001) with no evidence of publication bias (P=.24) but with significant heterogeneity among studies (I2=96%; Q=224.46; P<.001). Six studies provided data on cardiovascular disease (CVD) and 5 on cancer (in a total of 35,920 and 12,119 athletes, respectively). When only CVD was considered as a cause of mortality, the pooled SMR was 0.73 (95% CI, 0.65-0.82; P<.001) with no evidence of bias (P=.68) or heterogenity among studies (I2=38%; Q=8.07; P=.15). The SMR for cancer was 0.60 (95% CI, 0.38-0.94; P=.03) with no evidence of bias (P=.20) despite a significant heterogeneity (I2=91%; Q=44.21; P<.001). ConclusionThe evidence available indicates that top-level athletes live longer than the general population and have a lower risk of 2 major causes of mortality, namely, CVD and cancer.

Fibroblast growth factor 23 and risk of all-cause mortality and cardiovascular events: A meta-analysis of prospective cohort studies

Fibroblast growth factor 23 (FGF23), a hormone that is secreted by osteoblasts, is an important regulator of phosphorus and vitamin D metabolism [1]. The past few years have seen a rapidly growing interest in testing the hypothesis that increased FGF23 level is an independent risk factor of mortality and cardiovascular disease (CVD). Cross-sectional studies have found higher circulating FGF23 concentrations were associated with severity of coronary artery disease (CAD) [2], prevalent CVD [3], left ventricular hypertrophy [4], total body atherosclerosis [5], endothelial dysfunction [6], and metabolic syndrome [7]. However, the reports from two nest case– control studies have been inconsistent; one concluded a positive association between FGF23 and mortality in hemodialysis patients [8], whereas the other concluded no association between FGF23 and risk of coronary heart disease (CHD) [9]. Recently, epidemiologic prospective cohort studies have investigated the link between FGF23 and risk of mortality and CVD events in different populations including kidney disease [10–17], diabetes [18], CAD patients [19], and community-based adults [20–23]. Some studies found a positive association, but the magnitudes of the association varied between these studies, and others reported no association. The inconsistent results of cohort studies prompted us to conduct a meta-analysis of prospective cohort studies to evaluate the association between FGF23 and risk of all-cause mortality and CVD events. We followed a standardized protocol and conducted and reported this analysis according to the guidelines of the Meta-analysis of Observation Studies in Epidemiology group [24]. We conducted a systematic literature search of PubMed database through November 2013 for relevant articles that reported the association between FGF23 and risk of all-cause mortality and CVD events. To avoid missing any relevant study, we also searched the bibliographies of retrieved papers and recent reviews in the field. We did our search by using the following medical subject headings and keywords, such as Fibroblast Growth Factor-23, FGF23, and cardiovascular diseases, coronary disease, myocardial infarction, myocardial ischemia, coronary stenosis, coronary restenosis, cerebrovascular disorders, stroke, heart failure, death, mortality, all-cause mortality, cardiovascular mortality, and cohort studies, prospective studies, and followup studies. No restrictions were imposed. Two reviewers (Y.X. and X.L.) independently screened the abstracts and titles of the search results and eliminated articles only if they did not meet pre-stated inclusion criteria. The same 2 reviewers independently evaluated the remaining full-text articles for eligibility on the basis of a predefined set of eligibility criteria. Disagreements were resolved by discussion. Studies were considered eligible if they met the following criteria: 1) the study was a full-text, published prospective cohort study; 2) the exposure of interest was plasma or serum FGF23 concentrations; 3) the outcome of interest was all-cause or cardiovascular mortality or CVD events, myocardial infarction, stroke, or heart failure; and 4) relative risk (RR) and the corresponding 95% confidence interval (CI) or sufficient data to calculate them were provided. In addition, studies were excluded if they met the exclusion criteria that the sample size of a study was less than 200 and the duration of followup was less than one year. Two reviewers independently abstracted data on participant characteristics and study results with adjustment factors by using a standardized data collection form. Discrepancies in data extraction between reviewers were resolved by consensus. We extracted any reported RRs, HRs, or incidence density ratios of outcomes and study characteristics for each trial. We also systematically assessed key indicators of study quality: methods of outcome adjudication and ascertainment that account for confounders and completeness of follow-up ascertainment. To calculate summary estimates and 95% CIs of the risk for FGF23, we pooled both RRs and HRs by using either fixed-effects models or, in the presence of heterogeneity, randomeffects models [25]. The presence of heterogeneity across studies was evaluated by using the Q statistic with a conservative p value of 0.10. Potential publication bias was evaluated by Begg and Egger tests at the p b 0.10 level of significance. All analyses were performed using STATA version 11.0 (StataCorp LP, College Station, Texas). A p value b 0.05 was considered statistically significant, except where otherwise specified.

Pulmonary Hypertension Due to Left Heart Disease

Pulmonary hypertension (PH) due to left heart disease, classified as group 2 according to the Dana Point 2008 classification, is believed to be the most common cause of PH and is associated with high morbidity and mortality. Epidemiological studies of group 2 PH are less exhaustive than for rarer causes of PH such as isolated pulmonary vasculopathies, but attention for this entity is growing rapidly. Group 2 PH may be caused by passive downstream elevation in left heart pressures or by a combination of the latter with pulmonary arteriolar pathologies. Improved understanding of the perturbations in pulmonary vascular structure and function that cause PH due to left heart disease is essential to reduce heart failure morbidity and mortality. In this review, epidemiology, mechanisms, diagnostic approaches, hemodynamic models, and clinical trials of heart failure complicated by group 2 PH are reviewed, along with a discussion of novel treatment strategies that are currently under investigation or hold promise for the future. Interest in group 2 PH has historically been confined to mitral valve disease and advanced stages of heart failure (HF), wherein clinical manifestations of right ventricular (RV) failure carry an extremely unfavorable prognosis.1⇓–3 Clinical recognition of group 2 PH has expanded, with recent studies demonstrating that increases in rest and exercise pulmonary arterial pressures may accompany normal aging4,5 and that patients with HF and preserved ejection fraction (HFpEF) frequently also display PH.6 Although left heart disease is believed to represent the most common form of PH, epidemiological data are less abundant in this group in comparison with others.7 The most recent European Guidelines define group 1 PH as a chronic elevation of a mean pulmonary arterial pressure ≥25 mm Hg in association with normal pulmonary capillary wedge pressure (PCWP; ≤15 mm Hg; …

No association between cigarette smoking and incidence of plasma cell myeloma: A meta‐analysis of 17 observational studies

Plasma cell myeloma (PCM) is a lymphoproliferative disorder characterized by the malignant growth of monoclonal plasma cells within the bone marrow. Although risk factors for the development of PCM have been identified, the etiology on the majority of patients with PCM remains unclear. Cigarette smoking has been postulated as a potential risk factor for lymphoid malignancies; however, the association with PCM is inconclusive. We have carried out a meta-analysis of observational studies to assess the relationship, if any, between cigarette smoking and PCM. A literature search through December 2011 rendered 4 prospective cohort and 13 case–control studies evaluating such association. Our categorical meta-analysis showed that there is no association between ever, current, and former smokers and PCM.This lack of association was maintained when analyzing by study design, study quality, and geographical area of report. Similarly, meta regression analysis showed no association with the number of cigarettes smoked per day. In conclusion, our meta-analysis shows that there is no relationship between cigarette smoking and an increased incidence of PCM. Future studies should focus on other potential risk factors for PCM.

Body mass index and susceptibility to knee osteoarthritis: A systematic review and meta-analysis

ObjectiveExcess bodyweight, expressed as increased body mass index, is associated with osteoarthritis risk, especially in weight bearing joints. However, the strength of the association was inconsistent. The study was conducted to quantitatively assess the association between body mass index and the risk of knee osteoarthritis and investigate the difference of the strength stratified by sex, study type and osteoarthritis definition. MethodsWe used published guidelines of the Meta-analysis of Observational Studies in Epidemiology Group (MOOSE) to perform the meta-analysis. The search strategy employed included computerized bibliographic searches of MEDLINE, PubMed, EMBASE, The Cochran Library and references of published manuscripts. Study-specific incremental estimates were standardized to determine the risk of knee osteoarthritis associated with a 5kg/m2 increase in BMI. ResultsTwenty-one studies were included in the study. The results showed that body mass index was significantly positive associated with osteoarthritis risk in knee site. A 5-unit increase in body mass index was associated with an 35% increased risk of knee osteoarthritis (RR: 1.35; 95%CI: 1.21, 1.51). Magnitude of the association was significantly stronger in women than that in men with significant difference (men, RR: 1.22; 95%CI: 1.19, 1.25; women, RR: 1.38; 95%CI: 1.23, 1.54; p=0.04). The summary effect size was 1.25(95%CI: 1.18, 1.32) in case-control studies and 1.37 (95%CI: 1.19, 1.56) in cohort studies (p=0.28). Body mass index was positively associated with knee osteoarthritis defined by radiography and/or clinical symptom (RR: 1.25, 95%CI: 1.17, 1.35) and clinical surgery (RR: 1.54, 95%CI: 1.29, 1.83). The latter tended to be stronger than the former (p<0.01). ConclusionIncreased body mass index contribute to a substantially increased risk of knee OA. The magnitude of the association varies by sex and OA definition.

Is Neonatal Jaundice Associated with Autism Spectrum Disorders: A Systematic Review

Using guidelines of the Meta-analysis of Observational Studies in Epidemiology Group, we systematically reviewed the literature on neonatal jaundice (unconjugated hyperbilirubinemia) and Autism Spectrum Disorder (ASD) in term and preterm infants. Thirteen studies were included in a meta-analysis. Most used retrospective matched case-control designs. There was significant heterogeneity (Q=31, p=0.002) and no evidence of publication bias (p=0.12). Overall, jaundice, assessed by total serum bilirubin (TSB), was associated with ASD (OR, 1.43, 95% CI 1.22-1.67, random effect model). This association was not found in preterms (OR 0.7, 95% CI 0.38-1.02) but deserves further investigation since other measures of bilirubin such as unbound unconjugated bilirubin may be better predictors of neurotoxicity than TSB in preterms.

A Naturally Occurring Mutation in ropB Suppresses SpeB Expression and Reduces M1T1 Group A Streptococcal Systemic Virulence

Epidemiological studies of group A streptococcus (GAS) have noted an inverse relationship between SpeB expression and invasive disease. However, the role of SpeB in the course of infection is still unclear. In this study we utilize a SpeB-negative M1T1 clinical isolate, 5628, with a naturally occurring mutation in the gene encoding the regulator RopB, to elucidate the role of RopB and SpeB in systemic virulence. Allelic exchange mutagenesis was used to replace the mutated ropB allele in 5628 with the intact allele from the well characterized isolate 5448. The inverse allelic exchange was also performed to replace the intact ropB in 5448 with the mutated allele from 5628. An intact ropB was found to be essential for SpeB expression. While the ropB mutation was shown to have no effect on hemolysis of RBC's, extracellular DNase activity or survival in the presence of neutrophils, strains with the mutated ropB allele were less virulent in murine systemic models of infection. An isogenic SpeB knockout strain containing an intact RopB showed similarly reduced virulence. Microarray analysis found genes of the SpeB operon to be the primary target of RopB regulation. These data show that an intact RopB and efficient SpeB production are necessary for systemic infection with GAS.

Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes

The objective of the study was to determine whether indomethacin used as a tocolytic agent is associated with adverse neonatal outcomes. We used published guidelines of the Metaanalysis of Observational Studies in Epidemiology Group (MOOSE) to perform the metaanalysis. The search strategy used included computerized bibliographic searches of MEDLINE (1966-2005), PubMed (1966-2005), abstracts published in Obstetrics and Gynecology (1991-2005), abstracts published in Pediatric Research (1991-2005), and references of published manuscripts. Study inclusion criteria were publication in English, more than 30 deliveries less than 37 weeks' gestation, and meeting diagnostic criteria for individual neonatal outcomes. Exclusion criteria included case reports, case series, and multiple publications from the same author. Metaanalysis was performed using random effects model if there were more than 2 observational studies for a specific outcome. Eggers test was performed to exclude publication bias. Sensitivity analysis was performed to evaluate the effect of antenatal steroid exposure, gestation, and recent antenatal indomethacin exposure (duration of 48 hours or more between the last dose and delivery). Fifteen retrospective cohort studies and 6 case-controlled studies met inclusion criteria. Antenatal indomethacin was associated with an increased risk of periventricular leukomalacia (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.3-3.1). Recent exposure to antenatal indomethacin was associated with necrotizing enterocolitis (OR, 2.2; 95% CI; 1.1-4.2). Antenatal indomethacin was not associated with intraventricular hemorrhage, patent ductus arteriosus, respiratory distress syndrome, bronchopulmonary dysplasia, and mortality. Antenatal indomethacin may be associated with an increased risk of periventricular leukomalacia and necrotizing enterocolitis in premature infants and therefore should be used judiciously for tocolysis.

Typing of human isolates of Streptococcus agalactiae (group B streptococcus, GBS) strains from Zimbabwe.

Serotyping and genotyping are important tools in epidemiological studies of group B streptococcal (GBS) infections, which are important diseases in man, particularly in newborns. In the present study, 241 GBS isolates from Zimbabwe, comprising 124 carrier isolates from pregnant women and 117 isolates from patients hospitalised for various diseases, were serotyped. Antibodies specific for the capsular polysaccharide antigens (CPAs) Ia, Ib and II-V and antibodies specific for the surface-localised proteins, c(alpha), c(beta), R1, R3 and R4 were used for serotyping. Strains of the CPA types Ia (17%), III (47.7%) and V (23.2%) predominated. Of the various protein antigens, c(alpha) and R4 were expressed with highest frequency, c(alpha) by 100% of the CPA type Ia strains and R4 by 92% of the CPA type III strains. The R3 protein occurred frequently (24%), especially in type V strains (84%). A total of 25 serovariants was detected in the strain collection with the variants Ia/c(alpha) (16%), III/R4 (43.5%) and V/c(alpha), R3 (14.1%) occurring with the highest frequency. Serotype and subtype distribution of the carrier isolates were essentially similar to those of the disease-associated isolates. Genomic heterogeneity was demonstrated by pulsed-field gel electrophoresis of type III/R4 and type V/c(alpha), R3 isolates, but to a much lesser extent than recorded with Norwegian strains. These results demonstrate that many variants of GBS occur in the Zimbabwean population. The data obtained may assist in the formulation of a possible future GBS vaccine for Zimbabwe and perhaps for other African countries.

An epidemiological study of group A, B, C, and G hemolytic streptococci isolated from elementary school children in the recent 12 years. Part I. Isolation trends. Streptococcal Diseases Study Group

During a 12-years period between September, 1980 and November, 1992, hemolytic streptococci (group A, B, C, & G) in throats of healthy school children in Osaka were examined every other month. The results were summarized as follows. 1. 5,023 strains of hemolytic streptococci were detected from 11,647 specimens, 43.1%. Among them, 2,395 strains (20.6%) belonged to group A, 1,647 (14.4%) to group B, 767 (6.6%) to group G and 187 (1.6%) to group C. 2. In the first half of the research, group A streptococci were detected predominantly and the last half, group B generally. Both this lower rate of group A to the total strains (47.7%) and this higher rate of group B (33.3%) were due to the small number of lower school grade children from whom group A streptococci are often detected and also due to application of the selective enrichment medium. 3. Group A streptococci were classified T-type. The most common serotype was T-1, and 638 strains (26.6%) were detected, followed by T-12, 377 (15.7%), T-6, 210 (8.8%) and T-13, 203 (8.5%). The dominant serotype was exchanged annually, but only T-1 was the most common serotype for 4 years (1983-1986). 4. In group B, the most common serotype was Ia, and 524 strains (31.3%) were detected, followed by III, 417 (24.9%), Ib, 164 (9.8%), III/R, 130 (7.8%) and Ia/c 122 (7.3%). Annual changes of serotype were as follows; Ia was dominant from 1980 to 1988, III from 1989 to 1990 and NT6 in 1991-1992 generally.

In the Regulation of Manmade Carcinogens, If Feasibility Analysis Is the Answer, What Is the Question?

For more than a generation, cancer has been America's most feared disease. Cancer deaths are frequently long, debilitating, and inexorable. In addition to its toll on its immediate victims, cancer brings extended grief and, all too frequently, financial disaster to the families of its victims. In the early part of this century, the disease was not so singled out for attention tuberculosis, polio, bubonic plague, malaria, and measles all competed with cancer for attention as public health problems and for primacy in each citizen's private economy of dread. Now, medical science has largely mastered treatments and preventions for these other diseases, leaving cancer with fewer competitors.' Eliminating these rival sources of death has done more than simply leave cancer with fewer challengers; because people no longer die of these other afflictions, our life-spans have been increased sufficiently so that cancer, typically a disease of the middle-aged and elderly, has a much greater opportunity to claim its victims (pp. 17-18). Americans are convinced that our advances in science play another major role in cancer causation, thereby contributing to its prominence as a public concern in yet another way. Numerous chemicals now used throughout the American economy have been linked to cancer, either through epidemiological studies of groups with an abnormally high incidence of cancer, especially workers in chemical and chemicalrelated industries, or through laboratory experiments on animals. Many of these chemicals, such as the synthetic hydrocarbons that form the basis of the plastics industry, were literally unknown to the planet before the Second World War. Others, like asbestos, were not a substantial problem until industrial uses dramatically expanded their